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PubMed1981

Neural pathways mediating basal and stress-induced secretion of luteinizing hormone, follicle-stimulating hormone, and testosterone in the rat.

Adult male rats, intact or bearing complete, anterior, or posterior hypothalamic deafferentations (CHD, AHD, or PHD, respectively) or bilateral medial forebrain bundle (MFB) lesions, were acutely exposed to visual, audiogenic, or thermal stress. Two to 30 min after stress onset, the rats were decapitated, and trunk blood was collected from serum LH, FSH, and testosterone (T) determinations. While basal serum LH levels were found to be normal in all experimental groups, FSH levels were reduced in CHD and AHD rats, and serum T concentrations were found to be 3-fold greater than control values in the AHD group. In intact animals, exposure to all modalities caused significant elevations in serum levels of both LH and T, with no effect on FSH secretion. In the CHD and AHD groups, the LH and T responses were eliminated, with the exception of the T response to heat exposure, which persisted in CHD animals. In the PHD group, the LH and T responses persisted and were, in fact, potentiated. Bilateral medial forebrain bundle lesions inhibited the LH and T responses to audiogenic and thermal, but not to visual, stimulation. These data demonstrate that 1) basal FHS, but not LH, secretion is dependent upon extrahypothalamic afferents to the medial basal hypothalamus; 2) acute neurogenic stress stimulates LH and T, but not FSH, secretion; and 3) central nervous system sites, rostral to the medial basal hypothalamus, mediate the stress-induced elevations in LH release.

Acoustic Stimulation↗

PubMed1999

Transneuronal tracing of neural pathways controlling activity of diaphragm motoneurons in the ferret.

Previous studies have shown that neurons in addition to those in the medullary respiratory groups are involved in activating phrenic motoneurons during a number of behaviors, including vomiting and reaction to vestibular stimulation. However, the location of premotor inspiratory neurons outside of the main medullary respiratory groups is largely unknown, particularly in emetic species. In the present study, the transneuronal tracer pseudorabies virus was injected into the diaphragm of the ferret, and the locations of retrogradely-labeled motoneurons and transneuronally-labeled pre-motoneurons in the brainstem and cervical and thoracic spinal cord were mapped. Injections of a monosynaptic tracer, cholera toxin, were also made in order to verify the location of motoneurons innervating the diaphragm. Phrenic motoneurons identified with pseudorabies virus and cholera toxin were confined largely to the C5-C7 levels of spinal cord, and often gave rise to prominent polarized dendritic arbors that extended across the midline. At post-inoculation survival times > or = three days, transneuronally-labeled interneurons were located in the cervical and thoracic spinal cord and portions of the brainstem, including the midline pontomedullary reticular formation and the lateral medullary reticular formation. Double-labeling studies revealed that although the infected midline neurons were located in the proximity of serotonergic neurons, only a small number of the virus-containing cells were positive for serotonin. These findings suggest that neurons in the midline of the medulla and pons influence the activity of phrenic motoneurons, perhaps during inspiratory behaviors unique to emetic animals (such as vomiting).

Animals↗

PubMed1998

Volume expansion fails to normally activate neural pathways in the brain of conscious rabbits with heart failure.

Immunohistochemical detection of the protein, Fos, was used to identify neurons in the brain activated following a volume load in conscious rabbits with doxorubicin-induced congestive cardiomyopathy. The plasma expander, Haemaccel, was infused intravenously into rabbits for 60 min and significantly increased right atrial pressure, blood pressure and heart rate. The rabbits were perfusion fixed 90 min after the start of the infusion and the distribution of Fos-positive cell nuclei was examined. Compared to control rabbits with heart failure, there was a small significant increase in the number of Fos-positive cell nuclei in the organum vasculosum of the lamina terminalis following volume expansion. In other regions of the brain that were studied in detail, there were no significant increases in Fos production. These included the parvocellular paraventricular nucleus (PVN) of the hypothalamus, the midbrain periaqueductal gray, the nucleus tractus solitarius (NTS), area postrema and the ventrolateral medulla (VLM). In the supraoptic nucleus and the magnocellular PVN, no Fos-positive cell nuclei were present as expected. The median preoptic nucleus, the bed nucleus of the striae terminalis and the diagonal band of Broca contained some Fos but there was no marked difference between volume expanded and control animals. In the anterior cortical and medial subnuclei of the amygdala there was a high concentration of Fos but there was no consistent difference between the two groups. The present findings in heart failure rabbits suggest that most brain regions are not activated sufficiently by the stimulus to elicit Fos expression. The results are in accord with findings showing that sympathetic reflexes initiated by volume expansion are attenuated in heart failure.

Animals↗

PubMed1982

A 14C-2-deoxyglucose analysis of the neural pathways of the limbic forebrain in the rat: II. The hypothalamus.

An attempt was made to characterize the nature of the functional organization of the hypothalamus by observing the patterns of uptake of 14C-2-deoxyglucose (2DG) following electrical stimulation of different regions within the preoptico-hypothalamus in the rat. The experimental paradigm consisted of electrical brain stimulation delivered continuously for periods of 30 sec on and 30 sec off for 45 minutes following injection of 2DG. Brains were removed and processed for autoradiography. Activation of the medial forebrain bundle was noted following stimulation of the nucleus accumbens and lateral preoptico-hypothalamus. Activated fibers could be followed only in a caudal direction through the medial forebrain bundle and into the ventral tegmental area as a result of nucleus accumbens stimulation. Stimulation of the lateral preoptic region or of the anterior half of lateral hypothalamus produced activation of the lateral septal nucleus, lateral habenular nucleus, perifornical region, midline thalamus and ventral tegmental area. Since stimulation of the perifornical hypothalamus significantly activated the rostro-caudal extent of the midbrain cental gray, it is suggested that impulses from the lateral hypothalamus reach the lower brainstem via its connections with the perifornical hypothalamus. Ventromedial hypothalamic stimulation activated only the lateral septal nucleus, cortico-medial amygdala and medial preoptico-hypothalamus, while medial preoptico-hypothalamic stimulation resulted in increased 2DG uptake in the midbrain central gray, thus suggesting that medial hypothalamic impulses reach the brainstem by first ascending to the level of the preoptico-hypothalamus. Mammillary body stimulation orthodromically activated fibers in the mammillothalamic and mammillotegmental tracts and antidromically fibers in the fornix for a short distance.

Amygdala↗

PubMed1985

A [14C]2-deoxyglucose analysis of the functional neural pathways of the limbic forebrain in the rat. V. The septal area.

The [14C]2-deoxyglucose (2-DG) metabolic mapping technique has been used to identify the regions responding with an augmented rate of metabolism following focal electrical stimulation of various sites within the lateral septal nucleus and medial septal nucleus/diagonal band (MSN/DB) complex in the rat. Since 2-DG uptake has been correlated with rates of functional activity, it was the intention of this study to suggest the anatomical substrates underlying various physiological and behavioral responses elicited by stimulation of the septal area. The results show that stimulation of any region within the lateral septal nucleus produced a profound bilateral activation of both the lateral septal nucleus, as well as the hippocampal formation. While stimulation of a number of different fiber systems associated with the lateral septum could contribute to the observed pattern of labeling, the data suggest that, functionally, a major consequence of such stimulation is the antidromic activation of CA3----lateral septum fibers to axonal branch points, beyond which, orthodromic propagation of the impulse produces activation in CA3 target regions, including subfields CA1 and CA3, as well as the lateral septal nucleus, bilaterally. In addition, regions typically manifesting metabolic activation following stimulation of the lateral septal nucleus included the ipsilateral diagonal band of Broca, nucleus accumbens, lateral preoptic area and lateral hypothalamus, posteriorly, and the prelimbic cortex, anteriorly. Occasionally, target regions of the postcommissural fornix, including the medial mammillary nucleus and anterior thalamic nuclei were also activated following stimulation of the lateral septal nucleus. In contrast to the widespread pattern of activation resulting from stimulation of the lateral septal nucleus, stimulation of the MSN/DB complex produced activation which was largely confined to the medial forebrain bundle. In a final phase of the experiment, afterdischarge activity was elicited by sodium penicillin injection into the lateral septal nucleus. Such treatment produced more widespread 2-DG uptake, including more extensive activation within the lateral septal nucleus, hippocampal formation, amygdala, and thalamus. Additionally, the prefrontal cortex and temporal neocortex were activated.

Animals↗

PubMed1984

A [14C]2-deoxyglucose analysis of the functional neural pathways of the limbic forebrain in the rat. IV. A pathway from the prefrontal cortical-medial thalamic system to the hypothalamus.

The present study utilized the [14C]2-deoxyglucose (2-DG) cell labeling procedure to characterize a functional pathway from the prefrontal cortex (Pfc) and mediodorsal thalamic nucleus (MD) to the hypothalamus. Rats were injected with 2-DG prior to a 45 min experimental paradigm consisting of alternating 30 s on-off periods of electrical brain stimulation. Standard procedures were utilized for the removal and processing of brain tissue for X-ray autoradiography. In the first phase of this study, stimulation applied to the prefrontal cortex generally yielded a pattern of 2-DG distribution consistent with the findings of classical anatomical studies. Stimulation of the dorsomedial and ventromedial prefrontal cortex or the infralimbic cortex produced the most effective activation of the diencephalon. This activation was primarily limited to MD, with no involvement of any region of the hypothalamus. In the second phase of this study, brain regions activated following stimulation of sites along the rostro-caudal axis of MD were examined. Stimulation of MD resulted in the activation of the nucleus reuniens and other midline and non-specific thalamic nuclei. Stimulation of this nucleus also activated the ventromedial thalamic nucleus, medial aspects of the nucleus accumbens and the medial and sulcal prefrontal cortices. Again, in each of these cases, labeling within any region of the hypothalamus could not be detected. Since MD stimulation activated the midline thalamus, and the nucleus reuniens in particular, the last phase of this experiment involved stimulation of the nucleus reuniens in order to determine the source of medial thalamic inputs to the hypothalamus. Stimulation of the nucleus reuniens activated fibers which were distributed to both the medial and lateral hypothalamus. In addition, stimulation also activated the descending periventricular system, which could be followed to the level of the midbrain central gray and such limbic structures as the hippocampal formation, septal area, amygdala and prefrontal cortex. These findings indicate that Pfc-MD activation of the hypothalamus is achieved indirectly via interneurons within the nucleus reuniens.

Animals↗

PubMed1993

Evidence that distinct neural pathways mediate parasympathetic contractions and relaxations of guinea-pig trachealis.

1. The guinea-pig trachea was isolated with its extrinsic innervation intact and pinned to the bottom of a water-jacketed dissecting dish filled with warmed, oxygenated Krebs solution. The trachea was not separated from the oesophagus. Isometric tension was measured in a segment of the rostral portion of the trachea. 2. Stimulation of the vagus nerves caudal to the nodose ganglia elicited contractions of the trachealis that were blocked by the muscarinic receptor antagonist atropine. Following addition of atropine and contraction of the trachealis with prostaglandin F2 alpha (PGF2 alpha), vagus nerve stimulation elicited non-adrenergic, non-cholinergic relaxations. Both responses elicited by stimulation of the vagi were abolished by cutting the recurrent laryngeal nerves and were considered parasympathetic in nature as they were sensitive to the autonomic ganglion blockers trimetaphan and hexamethonium. 3. Experiments were designed in which ganglionic blockers were added to the buffer bathing the entire preparation or, alternatively, added only to the buffer perfusing the tracheal lumen. When given equal access to the trachea and oesophagus, hexamethonium was 56-fold more potent an inhibitor of vagally mediated relaxations of the trachealis than vagally mediated contractions. Selective administration of hexamethonium to the buffer perfusing the tracheal lumen did not decrease the potency of the ganglionic blocker versus vagally mediated contractions. By contrast, even at a concentration of 1 mM, intratracheally administered hexamethonium failed to inhibit vagally mediated relaxations by 50%. Comparable results were obtained using trimetaphan. 4. Consistent with previous observations, removing the portion of the oesophagus contiguous with the region of the trachea at which isometric tension was measured abolished parasympathetic relaxations of the trachealis. Oesophagus removal was without effect on parasympathetic nerve-induced contractions. Removing the dorsal half of the oesophagus or the mucosa and submucosa of the oesophagus did not affect the parasympathetic relaxant innervation. 5. The compound action potential of guinea-pig recurrent laryngeal nerves evoked by vagus nerve stimulation consisted of three distinct peaks representing populations of axons with fast, intermediate and slow conduction velocities. The voltage-response characteristics of vagally mediated contractions were identical to those of the compound action potential peak representing fibres with intermediate (10 m/s) conduction velocities. By contrast, the voltage-response characteristics of the vagally mediated relaxations were best correlated with the compound action potential peak representing fibres with slow (0.4-3 m/s) conduction velocities.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1998

Anatomy of the central neural pathways controlling the lower urinary tract.

OBJECTIVES: This paper will review the central nervous control of the lower urinary tract. METHODS: Neuroanatomical, electrophysiological and pharmacological techniques have provided information about the neural circuitry and the neurotransmitters involved in the neural control of voiding. RESULTS: Storage of urine is dependent in part upon spinal reflex mechanisms that activate sympathetic and somatic pathways to the urethral outlet as well as tonic inhibitory systems in the brain that suppress the parasympathetic outflow to the urinary bladder. Voiding is mediated by inhibition of sympathetic and somatic reflex pathways and activation of a spinobulbospinal parasympathetic reflex pathway passing through a micturition center in the rostral pons. Studies in animals indicate that glutamic acid is the major excitatory transmitter in the micturition reflex pathway and that a number of other transmitter mechanisms (noradrenergic, dopaminergic and GABAergic) modulate glutamatergic transmission. Damage to the brain or spinal cord can induce bladder hyperactivity by reducing central inhibitory mechanisms or by promoting a reorganization of spinal reflex pathways. CONCLUSIONS: The central nervous regulation of the lower urinary tract is mediated by simple on-off switching circuits in the brain and spinal cord that are under voluntary control. Interruption of central inhibitory mechanisms can unmask primitive voiding reflexes that trigger bladder hyperactivity.

Animals↗

PubMed1993

Separate neural pathways respond to different noxious stimuli affecting respiratory pump frequency in Aplysia fasciata.

Neural circuits responsible for both conditioned and unconditioned respiratory pumping to three stimuli modulating respiratory pumping were examined. The stimuli used were: (i) reduction of pH; (ii) increase and (iii) decrease in seawater concentration. Ablation of the osphradium, but not of the rhinophores, abolished responses to all 3 stimuli. Cutting the pleural-abdominal connectives led to a decrease in responses to lowered pH, but did not affect responses to changes in seawater concentration. Further lesions showed that integrity of the cerebral-pleural ganglion is needed for animals to respond to a decrease in pH. Thus, neural circuitry entirely within the abdominal ganglion and the periphery innervated by the ganglion is sufficient for mediating responses to changes in seawater concentration, while the cerebral ganglion is needed to respond to lowered pH. Different transmitter mechanisms are also used by pathways responding to changes in seawater concentration and to decreased pH: 5,7-dihydroxytryptamine in concentrations which cause depletion of serotonin blocked the response to lowered pH, but not to altered seawater concentrations.

5,7-Dihydroxytryptamine↗

PubMed1976

Afferent neural pathway in the regulation of cardiopulmonary responses to tissue hypermetabolism.

We studied the role of neural transmission from hypermetabolic peripheral tissues in the regulation of cardiac output and pulmonary ventilation in chloralose-anesthetized dogs. Cross-circulation techniques with femoral-femoral or femoral-aortic anastomoses were used to produce a vascularly isolated, but normally innervated, hindlimb or lower half-body, 2,4-Dinitrophenol (DNP) was infused into the arterial side of the perfusion circuit to triple oxygen consumption and to increase lactate production by the cross-perfused area. After infusion of DNP, cardiac output and mean systemic arterial blood pressure increased, but neither heart rate nor pulmonary artery wedge pressure changed significantly. Pulmonary minute ventilation and arterial pH also increased, while arterial PCO2 fell. These changes were abolished when the nerve connections between the perfused limb and its parent body were severed. Normal saline, when administered in a similar manner, did not increase either ventilation or cardiac output, and simple denervation without previous infusions of DNP also had no effect. These results indicate that there are receptors sensitive to metabolic changes in the tissue, and that neural transmission is an important afferent link in regulating the cardiopulmonary responses to increased tissue metabolism.

Afferent Pathways↗

PubMed1986

Neural pathways for the release of gastrin, cholecystokinin, and pancreatic polypeptide after a meal in dogs. Role of gastric and splanchnic nerves.

We have measured gastrin, cholecystokinin (CCK), and pancreatic polypeptide (PP) release after a meal in normal dogs under basal conditions and during atropine infusion, and after various neural sections. Denervation of the gastric antrum (antral vagotomy) abolished the early part of the gastrin response to food. Truncal vagotomy, celiac ganglionectomy, and atropine reduced the early release of CCK, which occurred before the start of gastric emptying, suggesting that a neural, cholinergic mechanism may release CCK immediately after a meal. PP release was abolished by truncal vagotomy, and also by antral vagotomy. As no direct pathways are known between the antrum and the pancreas, this suggests either that antral afferents are essential for this response or that vagally mediated hormone release from the antrum mediates PP release.

Animals↗

PubMed1995

Polysynaptic neural pathways from low threshold trunk cutaneous afferents to tail motoneurons in the spinalized cat.

Postsynaptic potentials (PSPs) after stimulating the cutaneous nerves of the trunk, dorsal cutaneous nerve (DC) and ventral cutaneous nerve (VC) were recorded from alpha-motoneurons innervating two tail muscles, the m. extensor caudae lateralis (ECL) and m. flexor caudae longus (FCL) in 22 spinalized (T10) cats. Stable recordings were obtained from 33 ECL and 42 FCL motoneurons. Stimulation of cutaneous nerves at 1.5-5 times threshold typically produced three types of synaptic effects in ECL and FCL motoneurons: predominant excitation (EPSP), or predominant inhibition (IPSP), or mixed effects characterized chiefly by early excitation followed by inhibition (EPSP/IPSP). The average central latencies of PSPs were distributed over a wide range (4.5-15.6 ms). Latency measurements indicated that most neural circuits from the trunk cutaneous afferents to the tail muscle motoneurons were oligosynaptic pathways via intraspinal slow-conducting fibers or polysynaptic pathways.

Afferent Pathways↗

PubMed1990

Neural pathways in chronic pain.

The evidence for changes in function of the central nervous system in cases of chronic pain is persuasive. We are not dealing with a passively wired system but one which changes structure and function and even connectivity in response to incoming sensory information. Whether these changes are capable of reversal with time and treatment remains to be shown. An optimist would suggest that physiological changes without abnormalities are indeed capable of reversal given time and appropriate neural input that matches normal non-painful afferent stimulation. That this is feasible is suggested by strategies of management with successful outcomes in patients with chronic pain, especially when pain is due to intermittent or limited ongoing stimulation of nociceptors. Clinical experience suggests, however, that deafferentation pain syndromes where pain is a consequence of damage directly to the nervous system cannot be viewed in such an optimistic light. A great deal more knowledge is required of how both the peripheral and central nervous system react to damage before we will be in a position to manage this source of chronic pain successfully.

Afferent Pathways↗

PubMed1993

Tracing neural pathways in snail olfaction: from the tip of the tentacles to the brain and beyond.

The anatomical organization of the olfactory system of terrestrial snails and slugs is described in this paper, primarily on the basis of experiments using the African snail Achatina fulica. Behavioral studies demonstrate the functional competence of olfaction in mediating food finding, conspecific attraction, and homing. The neural substrate for olfaction is characterized by an extraordinarily large number of neurons relative to the rest of the nervous system, and by the fact that many of them are unusually small. There exist multiple serial and parallel pathways connecting the olfactory organ, located at the tip of the tentacle, with integrative centers in the central nervous system. Our methods of studying these pathways have relied on the selective neural labels horseradish peroxidase and hexamminecobaltous chloride. One afferent pathway contains synaptic glomeruli whose ultrastructure is similar to that of the glomeruli seen in the mammalian olfactory bulb and the insect olfactory lobe. All of the olfactory neuropils, but especially the tentacle ganglion, contain large numbers of morphologically symmetrical chemical synapses. The procerebrum is a unique region of the snail brain that possesses further features analogous with olfactory areas in other animal groups. Olfactory axons from the tentacle terminate in the procerebrum, but the intrinsic neurons do not project outside of it. An output pathway from the procerebrum to the pedal ganglion has been identified and found to consist of inter-ganglionic dendrites. The major challenge for future studies is to elucidate the pattern of connectivity within, rather than between, the various olfactory neuropils.

Animals↗

PubMed1994

Separate neural pathways for the visual analysis of object shape in perception and prehension.

BACKGROUND: Earlier work with neurological patients has shown that the visual perception of object size and orientation depends on visual pathways in the cerebral cortex that are separate from those mediating the use of these same object properties in the control of goal-directed grasping. We present evidence suggesting that the same dissociation between perception and action is evident in the visual processing of object shape. In other words, discrimination between objects on the basis of their shape appears to be mediated by visual mechanisms that are functionally and neurally distinct from those controlling the pre-shaping of the hand during grasping movements directed at those same objects. RESULTS: We studied two patients with lesions in different parts of the cerebral visual pathways. One patient (RV), who had sustained bilateral lesions of the occipitoparietal cortex, was unable to use visual information to place her fingers correctly on the circumference of irregularly shaped objects when asked to pick them up, even though she had no difficulty in visually discriminating one such object from another. Conversely, a second patient (DF), who had bilateral damage in the ventrolateral occipital region, had no difficulty in placing her fingers on appropriate opposition points during grasping, even though she was unable to discriminate visually amongst such objects. CONCLUSIONS: This double dissociation lends strong support to the idea that the visual mechanisms mediating the perception of objects are functionally and neurally distinct from those mediating the control of skilled actions directed at those objects. It also supports the recent proposal of Goodale and Milner that visual perception depends on a ventral stream of projections from the primary visual cortex to the inferotemporal cortex, whereas the visual control of skilled actions depends on a dorsal stream from the primary visual cortex to the posterior parietal cortex.

Adult↗

PubMed1992

Efferent neural pathways of the lamina terminalis subserving osmoregulation.

Studies in rats and sheep show that neurons in the CVOs of the lamina terminalis provide extensive neural input to the vasopressin-containing cells of the supraoptic nucleus. This input is both by direct pathways and via a synapse in the MnPO which also has projections to the vasopressin-containing cells of the SON. Neurons throughout the lamina terminalis (including possible osmoreceptors in the OVLT and subfornical organ) are activated by systematic hypertonicity. It is likely that in response to hypertonicity they signal the SON and PVN to release vasopressin and elsewhere to elicit other osmoregulatory responses such as thirst and the excretion of sodium.

Animals↗

PubMed1990

Regulation of cholecystokinin secretion by food, hormones, and neural pathways in the rat.

Regulation of cholecystokinin (CCK) secretion was studied in conscious unrestrained rats by simultaneous duodenal perfusion with foodstuffs, intravenous infusion of hormones or neural agents, and arterial blood sampling for CCK bioassay. Duodenal infusion of casein resulted in elevation of plasma CCK from fasting level of 0.5 +/- 0.1 to 3.8 +/- 0.4 pM. Casein hydrolysate, calcium, and glucose did not elevate plasma CCK. Infusion of intact fat had a small, but nonsignificant, effect (1.4 +/- 0.4 pM), whereas infusion of oleate increased plasma CCK to 3.7 +/- 0.6 pM. Thus intact protein and fatty acids are the major dietary intestinal stimuli for CCK release in the rat. The CCK response to protein could be inhibited by somatostatin but not by peptide YY (0.2, 2, or 20 micrograms.kg-1.h-1); intravenous infusion of 1 or 10 micrograms.kg-1.h-1 somatostatin decreased casein-stimulated CCK levels to 1.5 +/- 0.2 and 0.9 +/- 0.3 pM, respectively. Stimulation of vagal discharge with 2-deoxy-D-glucose had no effect on basal or protein-stimulated plasma CCK levels; thus CCK release in the rat does not appear to be modulated by central vagal pathways. Gastrin-releasing peptide increased fasting plasma CCK levels to 1.6 +/- 0.1 pM. Administration of the cholinergic agonist bethanechol, while having no effect on fasting CCK level, inhibited protein-stimulated plasma CCK from 3.9 +/- 0.6 to 1.3 +/- 0.3 pM. Cholinergic blockade with atropine, in contrast, had no effect on basal or protein-stimulated plasma CCK. Thus CCK release is stimulated by dietary protein or fatty acid and by gastrin-releasing peptide and inhibited by somatostatin and bethanechol.

Animals↗

PubMed1989

States of developmental commitment of a mouse embryonal carcinoma cell line differentiating along a neural pathway.

The embryonal carcinoma cell line PCC7-S-AzaR1 (clone 1009) has been shown to differentiate in the presence of all-trans retinoic acid and dibutyryl cAMP into cells of predominantly neural properties (Paulin, D., H. Jakob, F. Jacob, K. Weber, and M. Osborn. 1982. Differentiation. 22:90-99). By analyzing the marker expression of derivatives in further detail, we characterized the two major cell phenotypes as neuron- and fibroblast-like and the two minor ones as astroglia- and endothelial-like. The stability of developmental commitment of clone 1009 was tested by recloning. The isolated subclones exhibited different patterns of chemically induced derivatives, with some of them (denoted N-clones) producing only a single (neuronal) cell type. As shown by long-term cultures in the absence of retinoic acid, the properties of isolated subclones remained essentially stable. In contrast to the clones producing neuron-like and other derivatives upon induced differentiation, the (exclusively neuronal) derivatives of N-clones detached and died within a few days in culture. If maintained in the presence of other neural cell types, however, their survival was dramatically extended indicating a requirement for specific interactions with other cells of the same tissue. The patterns of derivatives obtained from N-clones depended on the chemical nature of the substrate on which they were grown. Thus, when seeded on laminin-coated surfaces before induced differentiation, N-clones developed not only to neuron-like derivatives but rather to the same four derivatives observed with the original cell pool. These and further results suggest a common cell lineage of the identified phenotypes. The isolated subclones of uninduced cells probably represent different states of commitment within the same developmental pathway. Their stability offers the opportunity to analyze the nature of cellular commitment on the cellular, molecular, and genetic levels. This makes the family of clones derived from PCC7-S-AzaR1 (clone 1009) cells an advantageous in vitro model of mammalian brain early ontogenesis.

Animals↗